Does CerS3 in CD4+ T cells represent a new target for treating chronic inflammation and/or autoimmune diseases?

• Applicant: Professorin Dr. Sabine Grösch
• Subject Area: Pharmacology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556122536

T cells are an important part of the adaptive immune system and play a major role in the development and persistence of chronic inflammatory diseases such as ulcerative colitis, Crohn's disease, rheumatoid arthritis and multiple sclerosis. T cell activation occurs via the T cell receptor (TCR) at the cell membrane in so-called lipid rafts, which are cholesterol- and glycosphingolipid-enriched microdomains in the membrane. Lipid rafts influence the signaling processes of the TCR through their lipid composition. Ceramide synthase 3 (CerS3) is one of six human CerSs responsible for the chain-length specific synthesis of ceramides and complex sphingolipids such as glycosphingolipids. In our preliminary work, we have shown that the downregulation of CerS3 in CD4+ T cells is associated with massive changes in the sphingolipid profile of these cells. This project will investigate the influence of CerS3 on the functionality of CD4+ T cell lines (T helper cells (Th1, Th2, Th17, Th22, Th9), regulatory T cells (Treg) and follicular helper cells (Tfh)) in vitro and in the mouse. We will investigate the influence of CerS3 on the differentiation of these cells and how the localization and activity of membrane-bound and membrane-associated proteins are altered by CerS3 downregulation in CD4+ T cells. PhotoClick chemistry will be used to detect direct interaction of membrane proteins with sphingolipids. The influence of CerS3 downregulation on the migration of human CD4+ T cells will be analyzed in the organ-on-chip model. In mice with a CD4 T cell-specific deletion of CerS3, the effect of CerS3 deletion on the development and persistence of chronic inflammation such as ulcerative colitis, psoriasis or rheumatoid arthritis in vivo will be investigated. These studies should clarify whether CerS3 can be considered as a new target molecule in the therapy of chronic inflammation.

• DFG Programme: Research Grants